Human Airway Trypsin-Like Protease Increases Mucin Gene Expression in Airway Epithelial Cells

Chokki, Manabu; Yamamura, Satoshi; Eguchi, Hiroshi; Masegi, Tsukio; Horiuchi, Hideki; Tanabe, Hirofumi; Kamimura, Takashi; Yasuoka, Susumu

doi:10.1165/rcmb.2003-0199oc

Cited by 98 publications

(75 citation statements)

References 33 publications

(51 reference statements)

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“…These phenotypes are associated with the susceptibility of the T3D F S1 gene-encoded 1 protein to cleavage by the pancreatic serine proteases chymotrypsin and trypsin (8,9). While the respiratory tract contains comparably less protease activity than the gastrointestinal tract (47), injury or infection can lead to increases in protease expression in the lung (11,12,(14)(15)(16)(17)23). Inflammation in the respiratory tract may promote reovirus infection through recruitment of leukocytes and increased expression of inflammatory proteases capable of mediating extracellular reovirus disassembly (6,23).…”

Section: Effect Of T3dmentioning

confidence: 99%

“…Although high levels of secreted serine proteases are found in the gastrointestinal tract, protease expression in the respiratory tract is limited in the absence of inflammation (10). Following injury or infection of the respiratory tract, there is increased local expression of serine proteases, matrix metalloproteases, and inflammatory proteases (6,(11)(12)(13)(14)(15)(16)(17). Some of these proteases are capable of catalyzing reovirus uncoating (18-23).…”

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confidence: 99%

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Genetic Determinants of Reovirus Pathogenesis in a Murine Model of Respiratory Infection

Nygaard

Lahti

Ikizler

et al. 2013

J Virol

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Many viruses invade mucosal surfaces to establish infection in the host. Some viruses are restricted to mucosal surfaces, whereas others disseminate to sites of secondary replication. Studies of strain-specific differences in reovirus mucosal infection and systemic dissemination have enhanced an understanding of viral determinants and molecular mechanisms that regulate viral pathogenesis. After peroral inoculation, reovirus strain type 1 Lang replicates to high titers in the intestine and spreads systemically, whereas strain type 3 Dearing (T3D) does not. These differences segregate with the viral S1 gene segment, which encodes attachment protein 1 and nonstructural protein 1s. In this study, we define genetic determinants that regulate reovirus-induced pathology following intranasal inoculation and respiratory infection. We report that two laboratory isolates of T3D, T3D C and T3D F , differ in the capacity to replicate in the respiratory tract and spread systemically; the T3D C isolate replicates to higher titers in the lungs and disseminates, while T3D F does not. Two nucleotide polymorphisms in the S1 gene influence these differences, and both S1 gene products are involved. T3D C amino acid polymorphisms in the tail and head domains of 1 protein influence the sensitivity of virions to protease-mediated loss of infectivity. The T3D C polymorphism at nucleotide 77, which leads to coding changes in both S1 gene products, promotes systemic dissemination from the respiratory tract. A 1s-null virus produces lower titers in the lung after intranasal inoculation and disseminates less efficiently to sites of secondary replication. These findings provide new insights into mechanisms underlying reovirus replication in the respiratory tract and systemic spread from the lung. Many viruses enter host organisms by invading mucosal surfaces, including those that line the respiratory tract. Infection by some pneumotropic viruses is restricted to the respiratory tract, whereas others replicate in the lung and disseminate to sites of secondary replication. Mammalian orthoreoviruses (reoviruses) naturally infect both the respiratory and gastrointestinal tracts (1). Reovirus strains differ in the capacity to replicate at mucosal sites and disseminate systemically. Studies of strain-specific differences in reovirus mucosal infection and systemic spread have enhanced an understanding of viral determinants and molecular mechanisms that regulate reovirus pathogenesis. For example, after peroral or intratracheal inoculation, reovirus strain type 1 Lang (T1L) replicates to higher titers than does strain type 3 Dearing (T3D) (2). This difference in replication efficiency at the site of primary replication segregates with the reovirus S1 gene segment (2, 3). Like T1L, reassortant virus 3HA1, with nine gene segments from T3D and an S1 gene from T1L, replicates to high titers in mucosal tissues (2). In contrast, reassortant virus 1HA3, with nine gene segments from T1L and an S1 gene from T3D, fails to replicate to high titers at those sit...

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Section: Effect Of T3dmentioning

confidence: 99%

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confidence: 99%

Genetic Determinants of Reovirus Pathogenesis in a Murine Model of Respiratory Infection

Nygaard

Lahti

Ikizler

et al. 2013

J Virol

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“…14 The largest of the sub-families, HAT/DESC (Differentially Expressed in Squamous cell Carcinoma) consists of the proteases HAT, DESC1-4 10,41,42 and HATlike 3-5. 43 HAT was originally purified from the sputum of patients with chronic airway diseases 24 and is proposed to be associated with mucus production 44 and fibrin deposition within airways. 45 Further, elevated levels of HAT are present in the epidermis of psoriasis patients, suggesting an inflammatory role for this enzyme.…”

Section: The Type II Transmembrane Serine Proteasesmentioning

confidence: 99%

Matriptase-2 (TMPRSS6): a proteolytic regulator of iron homeostasis

Ramsay¹,

Hooper²,

Folgueras³

et al. 2009

Haematologica

107

104

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Maintaining the body's levels of iron within precise boundaries is essential for normal physiological function. Alterations of these levels below or above the healthy limit lead to a systemic deficiency or overload in iron. The type-two transmembrane serine protease (TTSP), matriptase-2 (also known as TMPRSS6), is attracting significant amounts of interest due to its recently described role in iron homeostasis. The finding of this regulatory role for matriptase-2 was originally derived from the observation that mice deficient in this protease present with anemia due to elevated levels of hepcidin and impaired intestinal iron absorption. Further in vitro analysis has demonstrated that matriptase-2 functions to suppress bone morphogenetic protein stimulation of hepcidin transcription through cell surface proteolytic processing of the bone morphogenetic protein co-receptor hemojuvelin. Consistently, the anemic phenotype of matriptase-2 knockout mice is mirrored in humans with matripase-2 mutations. Currently, 14 patients with iron-refractory iron deficiency anemia (IRIDA) have been reported to harbor various genetic mutations that abrogate matriptase-2 proteolytic activity. In this review, after overviewing the membrane anchored serine proteases, in particular the TTSP family, we summarize the identification and characterization of matriptase-2 and describe its functional relevance in iron metabolism.

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“…First, Dulon and colleagues (54) reported that NE inactivated PAR-2 in A549 and 16HBE14o -cells, and prevented subsequent activation by trypsin, a known agonist for PAR-2. Second, Chokki and coworkers (55) showed that human airway trypsin-like protease, but not a PAR-2-activating peptide, induced MUC2 and MUC5AC gene expression in NCI-H292 cells. Finally, PAR-2 expression was restricted to the basolateral surface of airway epithelial cells (56), which would render it inaccessible to NE released by luminal neutrophils on the apical side of respiratory mucosa.…”

Section: Discussionmentioning

confidence: 99%

The Signaling Pathway Involved in Neutrophil Elastase–Stimulated MUC1 Transcription

Kuwahara

Lillehoj²,

Koga³

et al. 2007

Am J Respir Cell Mol Biol

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We previously reported that neutrophil elastase (NE) stimulated MUC1 gene expression in A549 lung epithelial cells through binding of Sp1 to the MUC1 promoter element. The current study was undertaken to elucidate the complete signaling pathway leading to Sp1 activation. Using a combination of pharmacologic inhibitors, dominantnegative mutant, RNA interference, and soluble receptor blocking techniques, we identified a protein kinase Cd (PKCd) / dual oxidase 1 (Duox1) / reactive oxygen species (ROS) / TNF-a-converting enzyme (TACE) / TNF-a / TNF receptor (TNFR)1 / extracellular signal-regulated kinase (ERK)1/2 / Sp1 pathway as responsible for NE-activated MUC1 transcription. This cascade was identical up to the point of TACE with the signaling pathway previously reported for NE-stimulated MUC5AC production. However, unlike the MUC5AC pathway, TNF-a, TNFR1, ERK1/2, and Sp1 were unique components of the MUC1 pathway. Given the anti-inflammatory role of MUC1 during airway bacterial infection, up-regulation of MUC1 by inflammatory mediators such as NE and TNF-a suggests a crucial role for MUC1 in the control of excessive inflammation during airway bacterial infection.Keywords: neutrophil elastase; MUC1; signaling; airway MUC1 (MUC1 in human and Muc1 in nonhuman species) is a transmembrane mucin-like glycoprotein expressed on the surface of epithelial cells lining various mucosal surfaces, including the respiratory tract (1-3). We recently showed that mice deficient in Muc1 expression exhibited both enhanced airway inflammation and bacterial clearance during Pseudomonas aeruginosa (PA) airway infection (4), suggesting an anti-inflammatory role for Muc1 and the importance of Muc1 levels during airway bacterial infection. The anti-inflammatory activity of MUC1/Muc1 after treatment with bacterial products also was demonstrated in various in vitro studies (4). How the levels of MUC1/Muc1 are regulated during airway bacterial infection is unknown, but recent evidence indicates the involvement of neutrophil elastase (NE) (5).NE is present in micromolar concentrations in airway surface liquid of patients with cystic fibrosis and patients with chronic bronchitis (6, 7), and stimulates mucin release and mucin gene expression by cultured airway epithelial cells through the proteolytic activity (8, 9). Using a co-culture system containing hamster neutrophils and tracheal surface epithelial (TSE) cells, we demonstrated that activation of the neutrophils by fMLP or cytochalasin B resulted in the stimulation of mucin release (10), indicating that the concentrations of NE produced by activation of neutrophils are sufficient to release mucins. To date, NE is the most potent mucin secretagogue that has been described (11).In addition to gel-forming mucins such as MUC5AC, NE also induces the expression of the membrane-bound MUC1 and MUC4 mucins (5, 12). Our prior report showed that MUC1 protein synthesis by A549 cells was enhanced after treatment with NE, and this effect was blocked by pretreatment with actinomycin D or cycloheximide (...

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Human Airway Trypsin-Like Protease Increases Mucin Gene Expression in Airway Epithelial Cells

Cited by 98 publications

References 33 publications

Genetic Determinants of Reovirus Pathogenesis in a Murine Model of Respiratory Infection

Genetic Determinants of Reovirus Pathogenesis in a Murine Model of Respiratory Infection

Matriptase-2 (TMPRSS6): a proteolytic regulator of iron homeostasis

The Signaling Pathway Involved in Neutrophil Elastase–Stimulated MUC1 Transcription

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